In Pulmonary Arterial Hypertension, Reduced BMPR2 Promotes Endothelial-to-Mesenchymal Transition via HMGA1 and its Target Slug
Background—We previously reported high-throughput RNA sequencing analyses that identified heightened expression of the chromatin architectural factor High Mobility Group AT-hook 1 (HMGA1) in pulmonary arterial (PA) endothelial cells (ECs) from idiopathic PA hypertension (IPAH) patients compared to controls. Since HMGA1 promotes epithelial to mesenchymal transition in cancer, we hypothesized that increased HMGA1 could induce transition of PAECs to a smooth muscle (SM)-like mesenchymal phenotype (EndMT), explaining both dysregulation of PAEC function and possible cellular contribution to the occlusive remodeling that characterizes advanced IPAH.
Methods and Results—We documented increased HMGA1 in PAECs cultured from IPAH vs. donor control lungs. Confocal microscopy of lung explants localized the increase in HMGA1 consistently to PA endothelium, and identified many cells double-positive for HMGA1 and smooth muscle 22 alpha (SM22α) in occlusive and plexogenic lesions. Since decreased expression and function of bone morphogenetic protein receptor (BMPR)2 is observed in PAH, we reduced BMPR2 by siRNA in control PAECs and documented an increase in HMGA1 protein. Consistent with transition of PAECs by HMGA1, we detected reduced PECAM-1 (CD31) and increased EndMT markers, αSMA, SM22α, calponin, phospho-vimentin and Slug. The transition was associated with spindle SM-like morphology, and the increase in αSMA was largely reversed by joint knockdown of BMPR2 and HMGA1 or Slug. Pulmonary ECs from mice with EC-specific loss of BMPR2 showed similar gene and protein changes.
Conclusions—Increased HMGA1 in PAECs resulting from dysfunctional BMPR2 signaling can transition endothelium to SM-like cells associated with PAH.
- Received November 25, 2015.
- Revision received February 19, 2016.
- Accepted March 11, 2016.